This is a competing renewal for a project (DA007215-14) whose goal is to identify the structural requirements for cannabinergic activity through the synthesis of novel ligands aimed at modulating the function(s) of key cannabinergic proteins. These include the two cannabinoid receptors (CB1, CB2), the endocannabinoid deactivating enzymes (FAAH, MGL), and the transporter system (AT). This project has led to the development of key cannabinergic ligands currently in wide use by the research community, as well as novel drug leads. Recent developments in the field have motivated us to widen the project's scope to include monoacylglycerol lipase (MGL) as a novel cannabinergic target as well as azetidine analogs a promising new class of CB1 antagonists, allowing for the development of novel ligands and drugs with improved pharmacological profiles and broader therapeutic utility. We are also intensifying our efforts to develop improved 2AG analogs and probes, a goal that has not received due attention in the field. Our drug design and synthesis efforts encompass three approaches: 1) Novel cannabinoid analogs with improved water solubility and peripheral action. This will be accomplished through the introduction of heteroatoms in the cannabinoid side chain and tricyclic ring structures. 2) Novel 2-arachidonoyl glycerol (2AG) and arachidonoylethanolamine (AEA) analogs, with well-defined conformations. 3) Azetidine analogs representing a novel class of CB1 antagonists with improved pharmacological profiles. We shall study the stereoelectronic and physiochemical properties of the most successful novel compounds theoretically and by high-resolution NMR in solution and in membranes. Additionally, the nature of the ligand- receptor interaction will be explored through CB1 and CB2 receptor models. All new compounds will be tested for their affinities and functional properties (as agonists, antagonists or inverse agonists) for CB1 and CB2, while the endocannabinoid analogs will also be evaluated as substrates or inhibitors of FAAH, MGL and AT. The ability of the most successful compounds to cross the blood-brain barrier will be determined in vivo. The in vivo evaluation of key compounds will be carried out collaboratively at no cost to this grant. PUBLIC HEALTH RELEVANCE The development of medications to combat substance abuse and its myriad collateral ill-effects is of primary importance to NIDA and to national public health. Furthermore, the use of opioids as analgesic agents introduces serious abuse potential and invites development of analgesic medications with low or no abuse potential. The long-term goals of this application are to develop: (a) novel therapeutic medications for the treatment of cannabis, nicotine and stimulant abuse and (b) novel non-opioid analgesics devoid of undesirable side effects.